Sudjana-Sugiaman E, Eggertsen G, Björkhem I
Department of Clinical Chemistry, Karolinska Institute, Huddinge Hospital, Sweden.
J Lipid Res. 1994 Feb;35(2):319-27.
Among nine strains of rat, two were found that responded to phenobarbital treatment with increased activity of hepatic cholesterol 7 alpha-hydroxylase. This effect was maximal after 2-3 days of treatment and was then reduced. Interestingly the increased cholesterol 7 alpha-hydroxylase activity was associated with increased activity of hepatic HMG-CoA reductase in the two responding strains but not in the non-responding strains. In tissues other than the liver, HMG-CoA reductase activity was unaffected in responding rats. Most of the above stimulation occurred at a pretranslatory level and the mRNA levels corresponding to the two enzymes paralleled the activities. The phenobarbital treatment resulted in decreased content of free cholesterol in liver microsomes in a strain of rat that responded with increased cholesterol 7 alpha-hydroxylase activity. It was shown that depletion of cholesterol in the responding strain of rats by lymph fistulation also was associated with a parallel increase in levels of HMG-CoA reductase activity and mRNA. The findings are discussed in relation to the link between HMG-CoA reductase and cholesterol 7 alpha-hydroxylase. A primary upregulation of the cholesterol 7 alpha-hydroxylase by the cytochrome P450 inducer phenobarbital can be expected to lead to increased consumption of cholesterol substrate. This consumption may result in a compensatory increase in the activity of the HMG-CoA reductase. It is suggested that such a mechanism is responsible for part of the covariation of the two enzyme systems under different conditions.
在九只大鼠品系中，发现有两只对苯巴比妥治疗有反应，其肝脏胆固醇7α-羟化酶活性增加。这种效应在治疗2 - 3天后达到最大，然后降低。有趣的是，在这两个有反应的品系中，胆固醇7α-羟化酶活性的增加与肝脏HMG-CoA还原酶活性的增加相关，而在无反应的品系中则没有这种相关性。在肝脏以外的组织中，有反应的大鼠的HMG-CoA还原酶活性未受影响。上述大多数刺激发生在翻译前水平，与这两种酶相对应的mRNA水平与活性平行。苯巴比妥治疗导致在一个对胆固醇7α-羟化酶活性增加有反应的大鼠品系中，肝脏微粒体中游离胆固醇含量降低。结果表明，通过淋巴造瘘使有反应的大鼠品系中的胆固醇耗竭，也与HMG-CoA还原酶活性和mRNA水平的平行增加相关。结合HMG-CoA还原酶与胆固醇7α-羟化酶之间的联系对这些发现进行了讨论。细胞色素P450诱导剂苯巴比妥对胆固醇7α-羟化酶的原发性上调有望导致胆固醇底物消耗增加。这种消耗可能导致HMG-CoA还原酶活性的代偿性增加。有人提出，这种机制是不同条件下这两种酶系统共变的部分原因。
